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Process for preparing 6-aryl-4H-S-triazolo[3,4-c]-thieno[2,3-e]-1,4-diazepines

a technology of triazolo[3,4-c]-thieno[2,3-e]-1,4-diazepines and process, which is applied in the field of process for preparing 6aryl4hstriazolo3, 4cthieno2, 3e1, 4diazepines, can solve the problems of contamination of products and unsuitable industrial production

Inactive Publication Date: 2005-04-26
BOEHRINGER INGELHEIM PHARM KG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the preparation described therein, starting from a 5-aryl-1,3-dihydrothieno[2,3-e]-1,4-diazepin-2-one of formula II, is unsuitable for production on an industrial scale, as the intermediate products involved, such as for example 5-aryl-1,3-dihydrothieno[2,3-e]-1,4-diazepin-2-thiones, have to be isolated, and when reacted give off foul-smelling and in some cases toxic thiols which may lead to contamination of the products.

Method used

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  • Process for preparing 6-aryl-4H-S-triazolo[3,4-c]-thieno[2,3-e]-1,4-diazepines
  • Process for preparing 6-aryl-4H-S-triazolo[3,4-c]-thieno[2,3-e]-1,4-diazepines
  • Process for preparing 6-aryl-4H-S-triazolo[3,4-c]-thieno[2,3-e]-1,4-diazepines

Examples

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example 1

7-Bromo-5-(2-chlorophenyl)-1,3-dihydrothieno[2,3-e]-1,4-diazepine-2-one, (1)

[0066]220 g (0.746 mol) of 2-amino-N-[3-(2-chlorobenzoyl)thiophen-2-yl]acetamide (prepared by reacting 2-amino-3-(2-chlorobenzoyl)thiophene with bromoacetylbromide and subsequently piping in gaseous ammonia) are added at 110° C. to a mixture of 1.8 l of n-butanol and 150 ml of glacial acetic acid. The mixture is refluxed for 1 hour, cooled to ambient temperature and 330 ml of pyridine and 57 ml (178.8 g, 1.12 mol) of bromine are added with cooling. Then the mixture is stirred for another 0.5 to 2 hours, cooled to 5 to 10° C. and stirred for a further 2 hours at this temperature. The product that crystallises out is isolated by filtration, washed with 50% ethanol and dried overnight in vacuo at 60° C.

[0067]Yield: 152 g (57.3%).

example 2

Brotizolam

[0068]A suspension of 50 g (0.14 mol) of (1) in 2.5 ml of pyridine and 200 ml of dichloromethane is added dropwise to a suspension of 36 g (0.183 mol) of phosphorus pentachloride in 250 ml of dichloromethane at 5-10° C. with cooling. The mixture is stirred for 1 hour at 10° C. and a solution of 17 g (0.28 mol) of acetic acid hydrazide in 170 ml of tetrahydrofuran, heated to 40-50° C., is added dropwise with cooling at 10-20° C. The mixture is then stirred for 1 hour at ambient temperature and then refluxed for 5 to 18 hours. It is then cooled to ambient temperature, 380 ml water are added with cooling and the mixture is adjusted to an alkaline pH with 45% sodium hydroxide solution. The phases are separated and the aqueous phase is extracted with 100 ml of dichloromethane. 5 g of activated charcoal are added to the combined organic phases which are then stirred for 10 minutes, filtered and evaporated to dryness in vacuo. The residue is taken up in 750 ml of boiling methylet...

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Abstract

An improved process for preparing 6-aryl-4H-s-triazolo[3,4-c]-thieno[2,3-e]-1,4-diazepines of formula I, wherein:R1 is a hydrogen or halogen atom or a C1-C6 alkyl group,R2 is a hydrogen or halogen atom or a C1-C6 alkyl, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl group or a 5- or 6-membered oxygen-, sulphur- or nitrogen-containing heterocyclic group which may optionally be substituted at the nitrogen atom by a C1-C3 alkyl group, andR3 is a hydrogen or halogen atom.

Description

RELATED APPLICATIONS[0004]Benefit of U.S. Provisional Application Ser. No. 60 / 289,880, filed on May 9, 2001, is hereby claimed.FIELD OF THE INVENTION[0005]The invention relates to a process for preparing 6-aryl-4H-s-triazolo[3,4-c]-thieno[2,3-e]-1,4-diazepines of formula I, wherein R1, R2 and R3 have the meanings given, from a 5-aryl-1,3-dihydrothieno[2,3-e]-1,4-diazepin-2-one of formula II BACKGROUND OF THE INVENTION[0006]6-Aryl-4H-s-triazolo[3,4-c]-thieno[2,3-e]-1,4-diazepines, particularly brotizolam (R1=Br, R2=methyl, R3=Cl), are known for example from U.S. Pat. No. 4,094,984 and are valuable medicaments which have sedative properties, in particular, and may be used for treating sleep disorders.[0007]However, the preparation described therein, starting from a 5-aryl-1,3-dihydrothieno[2,3-e]-1,4-diazepin-2-one of formula II, is unsuitable for production on an industrial scale, as the intermediate products involved, such as for example 5-aryl-1,3-dihydrothieno[2,3-e]-1,4-diazepin-...

Claims

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Application Information

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IPC IPC(8): C07D495/04C07D495/14C07D495/00
CPCC07D495/14C07D495/04
Inventor BELZER, WERNERLOCK, RALF
Owner BOEHRINGER INGELHEIM PHARM KG
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